Fully Biocompatible Tantalum‐Based Antioxidant Nanoshields for Proximal Tubule Epithelial Cells‐Targeted Mitochondrial Holistic Protection in Acute Kidney Injury

Abstract Acute kidney injury (AKI) has an alarmingly high annual incidence. Heterogeneous AKI shares a common pathological hallmark—excessive reactive oxygen species (ROS), primarily generated from damaged proximal tubular epithelial cells (PTECs). Toxic ROS overload triggers mitochondrial dysfunction and excessive inflammation, initiating pathological crosstalk and vicious cycles that exacerbate AKI progression. However, many emerging preclinical therapeutic strategies or nanotechnologies face obstacles, including poor biocompatibility, inadequate targeting, and/or complex assembly, which hinder drug delivery and clinical translation. To address these limitations, fully‐biocompatible tantalum‐based antioxidant nanoshields (fTANS) with megalin (PTECs receptor)‐mediated active targeting have been developed. fTANS combine the elegant delivery capability from albumin coating with the superior ROS‐scavenging efficiency from reduced tantalum. fTANS traverse the glomerular filtration barrier with ultra‐small particle size and actively internalize into PTECs via the affinity between megalin and albumin, sequentially targeting mitochondria due to their mitochondrial affinity. By modulating ROS signals, fTANS effectively preserve mitochondria, thereby limiting cytochrome c ‐induced apoptosis and mitochondrial DNA‐triggered cGAS/STING‐mediated sterile inflammation, ultimately leading to effective treatment in AKI models. Following treatment, fTANS are cleared via renal excretion without observable toxicity, exhibiting remarkable biocompatibility. Collectively, this work represents a compelling advancement in targeted antioxidant nanomedicine, offering a promising avenue for AKI treatment.